Large-scale evidence for an association between low-grade peripheral inflammation and brain structural alterations in major depression in the BiDirect study

Large-scale evidence for an association between low-grade peripheral inflammation and brain structural alterations in major depression in the BiDirect study

J Psychiatry Neurosci 2019;44(6):423-431 | PDF | Appendix

Nils Opel, MD*; Micah Cearns, BPsy*; Scott Clark, PhD; Catherine Toben, PhD; Dominik Grotegerd, PhD; Walter Heindel, MD; Harald Kugel, PhD; Anja Teuber, PhD; Heike Minnerup, MD; Klaus Berger, MD; Udo Dannlowski, PhD†; Bernhard T. Baune, PhD†

Background: Preliminary research suggests that major depressive disorder (MDD) is associated with structural alterations in the brain, as well as with low-grade peripheral inflammation. However, even though a link between inflammatory processes and altered brain structural integrity has been purported by experimental research, well-powered studies to confirm this hypothesis in patients with MDD have been lacking. We aimed to investigate the potential association between structural brain alterations and low-grade inflammation as interrelated biological correlates of MDD.

Methods: In this cross-sectional study, 514 patients with MDD and 359 healthy controls underwent structural MRI. We used voxel-based morphometry to study local differences in grey matter volume. We also assessed serum levels of high-sensitivity C-reactive protein (hsCRP) in each participant.

Results: Compared with healthy controls (age [mean ± standard deviation] 52.57 ± 7.94 yr; 50% male), patients with MDD (49.14 ± 7.28 yr, 39% male) exhibited significantly increased hsCRP levels (Z = −5.562, p < 0.001) and significantly decreased grey matter volume in the prefrontal cortex and the insula. Prefrontal grey matter volume reductions were significantly associated with higher hsCRP levels in patients with MDD (x = 50, y = 50, z = 8; t1,501 = 5.15; k = 92; pFWE < 0.001). In the MDD sample, the significant negative association between hsCRP and grey matter appeared independent of age, sex, body mass index, current smoking status, antidepressant load, hospitalization and medical comorbidities. Limitations: This study had a cross-sectional design.

Conclusion: The present study highlights the role of reduced grey matter volume and low-grade peripheral inflammation as interrelated biological correlates of MDD. The reported inverse association between peripheral low-grade inflammation and brain structural integrity in patients with MDD translates current knowledge from experimental studies to the bedside.

*Contributed equally as first authors.

†Contributed equally as senior authors.

Submitted Nov. 1, 2018; Revised Nov. 29, 2018; Accepted Mar. 7, 2019; Published online July 15, 2019

Affiliations: From the Department of Psychiatry and Psychotherapy, University of Münster, Germany (Opel, Grotegerd, Dannlowski, Baune) the Interdisciplinary Centre for Clinical Research (IZKF), University of Münster, Germany (Opel); the Discipline of Psychiatry, School of Medicine, University of Adelaide, Australia (Cearns, Clark, Toben); the Institute of Clinical Radiology, University of Münster, Germany (Heindel, Kugel); the Institute of Epidemiology and Social Medicine, University of Münster, Germany (Teuber, Minnerup, Berger); the Department of Psychiatry, Melbourne Medical School, the University of Melbourne, Victoria, Australia (Baune); and the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia (Baune).

Funding: BiDirect is funded by the German Federal Ministry of Education and Research (grants 01ER0816, 01ER1506 and 01ER1205). This work was additionally funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 ; SFB-TRR58, Projects C09 and Z02) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 and SEED 11/18 to NO) and the Deanery of the Medical Faculty of the University of Münster. B. Baune receives funding from the National Health and Medical Research Council (NHMRC) Australia and from various foundations (Fay Fuller Foundation; James and Diana Ramsay Foundations).

Competing interests: B. Baune is member of advisory boards, received funding and/or gave presentations for AstraZeneca, Lundbeck, Janssen, Pfizer, Servier, and Wyeth, outside the submitted work. No other competing interests declared.

Contributors: N. Opel, M. Cearns, H. Kugel, K. Berger, U. Dannlowski and B. Baune designed the study. W. Heindel, H. Kugel, A. Teuber, H. Minnerup and K. Berger acquired the data, which N. Opel, M. Cearns, S. Clark, C. Toben, D. Grotegerd and U. Dannlowski analyzed. N. Opel, M. Cearns and U. Dannlowski wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.180208

Correspondence to: N. Opel, Department of Psychiatry, University of Münster, Albert-Schweitzer-Str. 11, 48149 Münster, Germany;